Significant progress has been made with the advent of multiple-combination drug therapy to prolong the lives of AIDS patients. However, the presence of latently infected, resting CD4 cells carrying replication-competent HIV has been demonstrated in chronically infected individuals who are antiretroviral naive as well as in those who are receiving highly active antiretroviral therapy (HAART). The failure to target the latently infected resting cells is a major impediment in drug therapy. One evolving therapy to combat HIV infection is gene therapy, which involves the introduction of anti-HIV genes to inhibit viral gene expression thereby limiting the HIV replication. Many different anti-HIV gene therapy approaches have been established to inhibit virus replication and the strategy has propelled to the forefront of developmental therapies for HIV infection. Although these studies are encouraging, development of a safe and efficient vector to deliver the antiviral genes still remains a challenge. The current vectors utilized in clinical trials for HIV gene therapy are inefficient as they cannot be propagated in non-dividing cells or their genome does not efficiently integrate into host DNA. Vectors based on lentiviruses such as HIV are promising since they can infect both dividing and non-dividing cells. Although the feasibility of lentiviruses in human gene therapy is still being explored using animal models, lentivirus vectors suffer from the potential risk of causing disease in humans. Vectors based on animal lentiviruses have been implicated as an alternative to HIV vectors for human gene therapy. However, the recent report that FIV can infect non-human primates with clinical signs indicates the risk associated with the usage of animal lentivirus based vectors for human gene therapy. Furthermore, even though lentivirus vectors can achieve effective and sustained transduction and expression in non-dividing cells they cannot efficiently transduce resting CD4 cells, where HAART therapy failed. Foamy viruses have several inherent features that make them an ideal vector system. The current proposal is a continuation in the development of novel foamy virus vectors for effective antiviral therapy against simian immunodeficiency virus (SIV) in severe combined immunodeficiency (SCID) mice. Studies from this proposal will help devise protocols for SFV-1 vector mediated gene therapy against SIV infection in monkeys and eventually for HIV infection in humans. [unreadable] [unreadable] [unreadable]